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Ultragenyx Pharmaceutical Inc. (Nasdaq: RARE) announced positive interim data from the ongoing pediatric Phase 2 study of KRN23 for the treatment of X-linked hypophosphatemia (XLH), demonstrating that serum phosphorus levels, rickets, growth rates and other functional outcomes improved with continued KRN23 treatment. The bi-weekly dose regimen continued to show a better overall response than patients who were dosed every four weeks, and patients with higher rickets at baseline showed greater improvements in bone disease and growth velocity. Data were also presented from the adult Phase 2 study of KRN23 for the treatment of XLH, demonstrating a significant increase in serum phosphorus levels and evidence of clinical improvement in walking, mobility, pain and stiffness at 24 weeks of treatment. Adverse events were consistent with what has been previously observed for KRN23 for the treatment of XLH. Ultragenyx is conducting the program under a collaboration and license agreement with Kyowa Hakko Kirin to develop and commercialize KRN23. Data from the two studies were presented today at the American Society for Bone and Mineral Research (ASBMR) 2016 Annual Meeting.

“Patients with XLH suffer from substantial bone disease, pain and stiffness throughout the entire course of their lives,” said Emil D. Kakkis, M.D., Ph.D., Chief Executive Officer and President of Ultragenyx. “These data support the potential for KRN23 to treat XLH in both pediatric and adult patients, who all experience significant burden of disease and are in need of new treatment options.”

"The accrued data from the ongoing KRN23 trials in children affected with XLH provide encouraging expectations for improving therapeutic outcomes in this condition,” commented Tom Carpenter, M.D., the lead investigator in this study. “It has become more evident that the responses to KRN23 therapy observed in patients have the potential to transform the treatment of XLH.”

Phase 2 Pediatric Study

The randomized, multicenter, open-label, dose finding study enrolled 52 patients ages five through 12, 49 of whom had been on currently available therapy (oral phosphate/active Vitamin D therapy) for an average of approximately seven years prior to entering the study. The first 36 patients enrolled in the study have completed the full 64-week dose-titration and treatment period. A subset of these patients (n=18) were pre-specified as having higher rickets (greater bone disease), defined by baseline total RSS scores of > 1.5. An additional 16 patients with higher rickets have completed 40 weeks of treatment.

Rickets severity was assessed at 40 weeks (n=52) and 64 weeks (n=36) using the RSS scoring system. Rickets improved significantly in all groups, with the greatest improvements in patients with higher baseline rickets (RSS ≥1.5) who received bi-weekly dosing of KRN23.

52 patients/40 weeks

Q2W

Overall

Q2W

Overall

RSS, All Patients

RSS, Higher BL RSS ≥ 1.5

n

26

52

n

17

34

% reduction (p < 0.0001)

61

%

50

%

% reduction (p < 0.0001)

71

%

61

%

36 patients/64 weeks

RSS, All Patients

RSS, Higher BL RSS ≥ 1.5

n

18

36

n

9

18

% reduction (p < 0.0001)

51

%

38

%

% reduction (p < 0.0001)

57

%

51

%

Radiographic Global Impression of Change (RGI-C) Scale

The change in the severity of rickets was also assessed at 40 and 64 weeks by the RGI-C score. Data show significant improvement in rickets in all groups. Substantial healing (RGIC score > 2) was observed in all but one patient with higher baseline rickets who received bi-weekly dosing.

Functional disability scores were measured with the Pediatric Orthopedic Society North America/Pediatric Outcome Data Collection Instrument (POSNA/PODCI). When evaluating the Global score of all five domains in those patients with substantial impairment at baseline (n=28, defined as baseline scores < 40 or one standard deviation below the normalized score of 50), a mean improvement of +17.5 (p< 0.0001) was observed at 40 weeks. Though the magnitude of these changes in functional measurements are substantial, any conclusions must be tempered by the fact that these data are from an uncontrolled, open-label study.

Safety and Tolerability

The most common treatment-related adverse events reported by preferred term was injection site reaction in 33% of patients. All of these reactions were considered mild. All other treatment-related adverse events were also considered mild. There was one serious adverse event considered possibly treatment-related. This was a previously reported patient with fever and muscle pain who improved without complication and is still in the trial. There have been no deaths or discontinuations from the study for any reason. No clinically meaningful changes were observed in mean serum calcium, urinary calcium and in serum intact parathyroid hormone. None of the patients had serum phosphorus levels above the upper limit of normal at any time point. No clinically significant changes were observed in renal ultrasounds pre- and post-treatment.

Phase 2 Adult Extension Study

The open-label, long-term extension study enrolled 20 adult patients with XLH who had previously participated in the phase 1 INT-001 or INT-002 studies of KRN23. All patients had at least a 12-month KRN23 treatment break before enrolling in the extension study. Patients who had resumed oral phosphate and active vitamin D therapy between studies (65%) completed a 21-day washout period. All patients began KRN23 treatment at the last dose received in the INT-001 or 002 study with an option to titrate during the first 12 weeks. An analysis of 24-week data is being presented.

At baseline, 19 of 20 patients had worst pain scores measured by the Brief Pain Inventory Question 3 (BPI-Q3) of > 4, classified as moderate to severe pain. The mean BPI-Q3 score was significantly reduced from baseline (p=0.0268; 1.1 point reduction from 6.6 at baseline to 5.5 at 24 weeks). These patients also demonstrated significant improvements in BPI pain interference (p=0.0009) and pain severity (p=0.0141) scores.

WOMAC pain, stiffness and physical function domain scores were significantly reduced at 24 weeks in these patients. Patients demonstrating the greatest improvements in stiffness (WOMAC stiffness responders) and pain (BPI-SF worst pain responders) had greater improvements in mobility tests, including the Timed Up and Go (TUG test for balance and agility) and the 6MWT. Mean patient TUG scores improved by 2 seconds (p=0.04) at week 24. At baseline, nearly all patients (19/20) were impaired in walking (defined by < 80% predicted normal walk distance in 6MWT). The mean increase in distance walked was 25 meters (p=0.05) from baseline.

Safety and Tolerability

The most common adverse events were arthralgia (30%), nasopharyngitis (25%), back pain (20%), injection site reaction (20%), and pain in extremity (20%). Treatment-related adverse events occurred in 40% of patients, and were all considered mild. None of the four serious adverse events were considered treatment-related. There have been no deaths or discontinuations from the study.

Conference Call Details

Ultragenyx will host a conference call on Monday, September 19 at 11am ET during which Dr. Kakkis will discuss results of the KRN23 studies being presented at the ASBMR Annual Meeting. The live and replayed webcast of the call will be available through the company's website at http://ir.ultragenyx.com/events.cfm. To participate in the live call by phone, dial 855-797-6910 (USA) or 262-912-6260 (international) and enter the passcode 83882106. The replay of the call will be available for one year.